Methods of operating dry powder inhalers having spiral travel paths with microcartridges of dry powder

ABSTRACT

Dry powder inhalers include: (a) a first generally planar spiral travel path in an inhaler body, wherein the first spiral travel path has a plurality of adjacent curvilinear channels forming lanes with upstanding sidewalls, including an inner lane and an outer lane; and (b) a plurality of discrete sealed microcartridges with substantially rigid bodies disposed in the first travel path, each comprising a pre-metered (typically dose) amount of dry powder, the microcartridges being configured to slidably advance along the first travel path toward an inhalation chamber that merges into an inhalation output port. In operation, at least one microcartridge is held in the inhalation chamber to release the dry powder therein during inhalation.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/625,855 filed Jan. 23, 2007, which claims the benefit of priority toU.S. Provisional Application Ser. No. 60/763,717, filed Jan. 31, 2006,the contents of which are hereby incorporated by reference as if recitedin full herein.

FIELD OF THE INVENTION

The present invention relates to drug containment and/or dispensingsystems suitable for dry powders formulated for delivery as inhalantaerosols.

BACKGROUND OF THE INVENTION

Dry powder inhalers (DPIs) represent a promising alternative topressurized pMDI (pressurized metered dose inhaler) devices fordelivering drug aerosols without using CFC propellants. See generally,Crowder et al., 2001: an Odyssey in Inhaler Formulation and Design,Pharmaceutical Technology, pp. 99-113, July 2001; and Peart et al., NewDevelopments in Dry Powder Inhaler Technology, American PharmaceuticalReview, Vol. 4, n. 3, pp. 37-45 (2001). Typically, the DPIs areconfigured to deliver a powdered drug or drug mixture that includes anexcipient and/or other ingredients.

Generally described, known single and multiple dose dry powder DPIdevices use: (a) individual pre-measured doses in blisters containingthe drug, which can be inserted into the device prior to dispensing; or(b) bulk powder reservoirs which are configured to administer successivequantities of the drug to the patient via a dispensing chamber whichdispenses the proper dose. See generally Prime et al., Review of DryPowder Inhalers, 26 Adv. Drug Delivery Rev., pp. 51-58 (1997); andHickey et al., A new millennium for inhaler technology, 21 Pharm. Tech.,n. 6, pp. 116-125 (1997).

In operation, DPI devices strive to administer a uniform aerosoldispersion amount in a desired physical form of the dry powder (such asa particulate size) into a patient's airway and direct it to a desireddeposit site(s).

A number of obstacles can undesirably impact the performance of the DPI.For example, the small size of the inhalable particles in the dry powderdrug mixture can subject them to forces of agglomeration and/or cohesion(certain types of dry powders are susceptible to agglomeration, which istypically caused by particles of the drug adhering together), which canresult in poor flow and non-uniform dispersion. In addition, as notedabove, many dry powder formulations employ larger excipient particles topromote flow properties of the drug. However, separation of the drugfrom the excipient, as well as the presence of agglomeration, canrequire additional inspiratory effort, which, again, can impact thestable dispersion of the powder within the air stream of the patient.Unstable dispersions may inhibit the drug from reaching its preferreddeposit/destination site and can prematurely deposit undue amounts ofthe drug elsewhere.

Further, some dry powder inhalers can retain a significant amount of thedrug within the device, which can be especially problematic over time.

Some inhalation devices have attempted to resolve problems attendantwith conventional passive inhalers. For example, U.S. Pat. No. 5,655,523proposes a dry powder inhalation device which has adeagglomeration/aerosolization plunger rod or biased hammer andsolenoid, and U.S. Patent No. 3,948,264 proposes the use of abattery-powered solenoid buzzer to vibrate the capsule to effectuate therelease of the powder contained therein. These devices propose tofacilitate the release of the dry powder by the use of energy inputindependent of patient respiratory effort. U.S. Pat. No. 6,029,663 toEisele et al. proposes a dry powder inhaler delivery system with arotatable carrier disk having a blister shell sealed by a shear layerthat uses an actuator that tears away the shear layer to release thepowder drug contents. U.S. Pat. No. 5,533,502 to Piper proposes a powderinhaler using patient inspiratory efforts for generating a respirableaerosol and also includes a rotatable cartridge holding the depressedwells or blisters defining the medicament-holding receptacles. Aspring-loaded carriage compresses the blister against conduits withsharp edges that puncture the blister to release the medication that isthen entrained in air drawn in from the air inlet conduit so thataerosolized medication is emitted from the aerosol outlet conduit. U.S.Pat. No. 6,971,383 to Hickey et al. and U.S. Pat. No. 6,889,690 toCrowder et al. describe using custom signals matched to a particular drypowder to facilitate fluidic delivery. The contents of all of thesepatents are hereby incorporated by reference as if stated in fullherein.

Notwithstanding the above, there remains a need for alternative inhalersand/or drug containment devices that can be used to deliver dry powdermedicaments.

SUMMARY OF EMBODIMENTS OF THE INVENTION

Dry powder inhalers include: (a) a first generally planar spiral travelpath in an inhaler body, wherein the first spiral travel path has aplurality of adjacent curvilinear channels forming lanes with upstandingsidewalls, including an inner lane and an outer lane; and (b) aplurality of discrete sealed microcartridges with substantially rigidbodies disposed in the first travel path, each comprising a pre-metereddose of dry powder, the microcartridges being configured to slidablyadvance along the first travel path toward an inhalation chamber thatmerges into an inhalation output port, wherein, in operation, at leastone microcartridge is held in the inhalation chamber to release the drypowder therein during inhalation.

Other embodiments are directed to dry powder inhalers that include: (a)first and second curvilinear travel paths in an inhaler body, at least amajor portion of one residing above the other, each curvilinear travelpath comprising a plurality of curvilinear side-by-side lanes on acommon plane, the curvilinear travel paths comprising a respectivedispensing lane that leads to an inhalation delivery chamber in fluidcommunication with an inhalation port; and (b) a plurality of discretemicrocartridges, each comprising a meted amount of dry powder, whereinmicrocartridges disposed in each of the first and second travel pathsnugly about neighboring microcartridges and slidably advance along therespective travel paths to the respective dispensing lane.

Still other embodiments are directed to methods of operating an inhalerto expel inhalable medicaments. The methods include: slidably advancinga plurality of snugly abutting sealed microcartridges loaded with ameted amount of a first dry powder along a first curvilinear channelassociated with a first travel path so that at least some of therespective loaded microcartridges travel greater than one revolution ina first level.

In particular embodiments, the method may optionally include directingthe loaded microcartridges to travel to a lower level for dispensing inan inhalation chamber after traveling greater than one revolution in thefirst level.

In some embodiments, the first travel path channel defines closelyspaced serially traveled spiraling travel lanes, wherein at least someof the microcartridges travel greater than 2 revolutions in a firstlevel in the spiraling lanes before moving to a second level fordispensing.

Additional embodiments are directed to methods of forming unit dosemicrocartridges for use in dry powder inhalers. The methods include: (a)providing a substantially rigid elastomeric microcartridge body; (b)inserting a meted amount of dry powder suitable for inhalation delivery;and (c) attaching a substantially rigid top to the body to seal the drypowder therein.

The methods may optionally include providing externally visible indiciaof dry powder type and/or dose amount on the body.

It is noted that aspects of the invention may be embodied as hardware,software or combinations of same, i.e., devices, methods and/or computerprogram products. These and other objects and/or aspects of the presentinvention are explained in detail in the specification set forth below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a side perspective view of an exemplary inhaler according toembodiments of the present invention.

FIG. 2A is a side perspective view of an internal portion of amulti-level inhaler with dual spiral travel paths according toembodiments of the present invention.

FIG. 2B is a schematic illustration of side-by-side spiral travel pathsaccording to other embodiments of the present invention.

FIG. 2C is a schematic illustration of an alternate spiral travel pathconfiguration according to other embodiments of the present invention.

FIG. 3A is a side view of an internal portion of a multi-level inhaleraccording to embodiments of the present invention.

FIG. 3B is a schematic side view of a portion of an inhaler withmulti-level queues of discrete drug containers according to embodimentsof the present invention.

FIG. 4A is an exploded top perspective view of an inhaler with acurvilinear drug travel path according to embodiments of the presentinvention.

FIG. 4B is an enlarged side perspective view of a portion of an inhaleraccording to embodiments of the present invention.

FIG. 4C is a cutaway view of a lower level of a multi-level inhaleraccording to some embodiments of the present invention.

FIG. 5 is a side perspective view of a portion of a dispensing floor ofa multi-level inhaler according to embodiments of the present invention.

FIG. 6A is a schematic illustration of an intake and release path fordispensing combination delivery inhalation medicaments in an inhaleraccording to embodiments of the present invention.

FIGS. 6B-6E are schematic illustrations of a sequence of operationsemploying an alternate intake and release path relationship according toembodiments of the present invention.

FIGS. 7 and 8 are schematic illustrations of a cutting operationaccording to embodiments of the present invention.

FIG. 9 is a flow chart of operations that can be used to operate aninhaler according to embodiments of the present invention.

FIG. 10 is a schematic illustration of a circuit for an inhaler usablefor a combination delivery system according to embodiments of thepresent invention.

FIG. 11A is an end perspective view of components of an inhaleraccording to embodiments of the present invention.

FIG. 11B is a side perspective view schematically illustrating aninternal trash bin according to embodiments of the present invention.

FIG. 12 is an end perspective view of components of an inhaler with aresilient member according to embodiments of the present invention.

FIG. 13 is a bottom perspective view of a linkage mechanism according toembodiments of the present invention.

FIG. 14 is an exploded view of a rotating cup assembly according toembodiments of the present invention.

FIGS. 15-17 are sequential views of operational positions of themechanical linkage shown in FIG. 13 according to embodiments of thepresent invention.

FIG. 18 is a front perspective view of a sealed microcartridge withmedicament (such as dry powder) according to embodiments of the presentinvention.

FIGS. 19A-19D are sequential cross-sectional views of exemplary fillingand sealing operations of the microcartridge shown in FIG. 18 accordingto embodiments of the present invention.

FIG. 20A is a top schematic view of a taped link of microcartridgesaccording to embodiments of the present invention.

FIG. 20B is a side perspective view of a strip of microcartridgesaccording to some embodiments of the present invention.

FIG. 21 is a flow chart of operations that can be used to fillmicrocartridges according to embodiments of the present invention.

DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention will now be described more fully hereinafter withreference to the accompanying figures, in which embodiments of theinvention are shown. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein. Like numbers refer to like elementsthroughout. In the figures, certain layers, components or features maybe exaggerated for clarity, and broken lines illustrate optionalfeatures or operations unless specified otherwise. In addition, thesequence of operations (or steps) is not limited to the order presentedin the figures and/or claims unless specifically indicated otherwise. Inthe drawings, the thickness of lines, layers, features, componentsand/or regions may be exaggerated for clarity and broken linesillustrate optional features or operations, unless specified otherwise.

It will be understood that when a feature, such as a layer, region orsubstrate, is referred to as being “on” another feature or element, itcan be directly on the other feature or element or intervening featuresand/or elements may also be present. In contrast, when an element isreferred to as being “directly on” another feature or element, there areno intervening elements present. It will also be understood that, when afeature or element is referred to as being “connected”, “attached” or“coupled” to another feature or element, it can be directly connected,attached or coupled to the other element or intervening elements may bepresent. In contrast, when a feature or element is referred to as being“directly connected”, “directly attached” or “directly coupled” toanother element, there are no intervening elements present. Althoughdescribed or shown with respect to one embodiment, the features sodescribed or shown can apply to other embodiments.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the relevant art andthis application and should not be interpreted in an idealized or overlyformal sense unless expressly so defined herein.

In the description of the present invention that follows, certain termsare employed to refer to the positional relationship of certainstructures relative to other structures. As used herein, the term“front” or “forward” and derivatives thereof refer to the general orprimary direction that the dry powder travels to be dispensed to apatient from a dry powder inhaler; this term is intended to besynonymous with the term “downstream,” which is often used inmanufacturing or material flow environments to indicate that certainmaterial traveling or being acted upon is farther along in that processthan other material. Conversely, the terms “rearward” and “upstream” andderivatives thereof refer to the direction opposite, respectively, theforward or downstream direction.

The term “sealant layer” and/or “sealant material” includesconfigurations that have at least one layer or one material; thus, sucha phrase also includes multi-layer or multi-material sealantconfigurations. The term “unitized” means a specified quantity of apharmaceutical drug and/or medicament in terms of which the magnitudesof other quantities of the same or different drug and/or medicament canbe stated.

The term “deagglomeration” and its derivatives refer to processing drypowder in the inhaler airflow path to inhibit the dry powder fromremaining or becoming agglomerated or cohesive during inspiration.

The term “microcartridge” and derivatives thereof refer to a disposabledrug container device that holds at least one unitized, meted and/orbolus amount of a target drug or medicament and may be also known as adrug containment system (“DCS”). The microcartridges can be configuredas relatively compact, generally tubular and/or cup-like containers witha cavity that is sized and configured to hold about 100 mg or less ofdry powder for inhalation delivery, typically less than 50 mg, and moretypically between about 0.1 mg to about 10 mg. In some embodiments, suchas for pulmonary conditions (i.e., asthma), the dry powder can beprovided as about 5 mg total weight (the dose amount may be blended toprovide this weight). The microcartridges can have sidewalls withsufficient rigidity to resist flexure and allow a ceiling to be sealablyattached thereto after filling. The microcartridges are configured toinhibit oxygen and moisture penetration. In particular embodiments, themicrocartridges can be configured to have a miniaturized “puck” shape,such that they may be wider than they are tall with a hollow interior orholding cavity. In other embodiments, the microcartridges may have asimilar height and width or may be taller than they are wide.

The term “free floating” refers to embodiments where the microcartridgesare detached (not connected) from each other.

The inhalers and methods of the present invention may be particularlysuitable for holding a partial or bolus dose or doses of one or moretypes of particulate dry powder substances that are formulated for invivo inhalant dispersion (using an inhaler) to subjects, including, butnot limited to, animal and, typically, human subjects. The inhalers canbe used for nasal and/or oral (mouth) respiratory inhalation delivery.

The dry powder substance may include one or more active pharmaceuticalconstituents as well as biocompatible additives that form the desiredformulation or blend. As used herein, the term “dry powder” is usedinterchangeably with “dry powder formulation” and means that the drypowder can comprise one or a plurality of constituents or ingredientswith one or a plurality of (average) particulate size ranges. The term“low-density” dry powder means dry powders having a density of about 0.8g/cm³ or less. In particular embodiments, the low-density powder mayhave a density of about 0.5 g/cm³ or less. The dry powder may be a drypowder with cohesive or agglomeration tendencies.

In any event, individual dispensable quantities of dry powderformulations can be a single ingredient or a plurality of ingredients,whether active or inactive. The inactive ingredients can includeadditives added to enhance flowability or to facilitate aerosolizationdelivery to the desired target. The dry powder drug formulations caninclude active particulate sizes that vary. The device may beparticularly suitable for dry powder formulations having particulateswhich are in the range of between about 0.5-50 μm, typically in therange of between about 0.5 μm-20.0 μm, and more typically in the rangeof between about 0.5 μm -8.0 μm. The dry powder formulation can alsoinclude flow-enhancing ingredients, which typically have particulatesizes that may be larger than the active ingredient particulate sizes.In certain embodiments, the flow-enhancing ingredients can includeexcipients having particulate sizes on the order of about 50-100 μm.Examples of excipients include lactose and trehalose. Other types ofexcipients can also be employed, such as, but not limited to, sugarswhich are approved by the United States Food and Drug Administration(“FDA”) as cryoprotectants (e.g., mannitol) or as solubility enhancers(e.g., cyclodextrine) or other generally recognized as safe (“GRAS”)excipients.

“Active agent” or “active ingredient” as described herein includes aningredient, agent, drug, compound, or composition of matter or mixture,which provides some pharmacologic, often beneficial, effect. Thisincludes foods, food supplements, nutrients, drugs, vaccines, vitamins,and other beneficial agents. As used herein, the terms further includeany physiologically or pharmacologically active substance that producesa localized and/or systemic effect in a patient.

The active ingredient or agent that can be delivered includesantibiotics, antiviral agents, anepileptics, analgesics,anti-inflammatory agents and bronchodilators, and may be inorganicand/or organic compounds, including, without limitation, drugs which acton the peripheral nerves, adrenergic receptors, cholinergic receptors,the skeletal muscles, the cardiovascular system, smooth muscles, theblood circulatory system, synoptic sites, neuroeffector junctionalsites, endocrine and hormone systems, the immunological system, thereproductive system, the skeletal system, autacoid systems, thealimentary and excretory systems, the histamine system, and the centralnervous system. Suitable agents may be selected from, for example andwithout limitation, polysaccharides, steroid, hypnotics and sedatives,psychic energizers, tranquilizers, anticonvulsants, muscle relaxants,anti-Parkinson agents, analgesics, anti-inflammatories, musclecontractants, antimicrobials, antimalarials, hormonal agents includingcontraceptives, sympathomimetics, polypeptides and/or proteins (capableof eliciting physiological effects), diuretics, lipid regulating agents,antiandrogenic agents, antiparasitics, neoplastics, antineoplastics,hypoglycemics, nutritional agents and supplements, growth supplements,fats, antienteritis agents, electrolytes, vaccines and diagnosticagents.

The active agents may be naturally occurring molecules or they may berecombinantly produced, or they may be analogs of the naturallyoccurring or recombinantly produced active agents with one or more aminoacids added or deleted. Further, the active agent may comprise liveattenuated or killed viruses suitable for use as vaccines. Where theactive agent is insulin, the term “insulin” includes natural extractedhuman insulin, recombinantly produced human insulin, insulin extractedfrom bovine and/or porcine and/or other sources, recombinantly producedporcine, bovine or other suitable donor/extraction insulin and mixturesof any of the above. The insulin may be neat (that is, in itssubstantially purified form), but may also include excipients ascommercially formulated. Also included in the term “insulin” are insulinanalogs where one or more of the amino acids of the naturally occurringor recombinantly produced insulin has been deleted or added.

It is to be understood that more than one active ingredient or agent maybe incorporated into the aerosolized active agent formulation and thatthe use of the term “agent” or “ingredient” in no way excludes the useof two or more such agents. Indeed, some embodiments of the presentinvention contemplate administering combination drugs that may be mixedin situ.

Examples of diseases, conditions or disorders that may be treatedaccording to embodiments of the invention include, but are not limitedto, asthma, COPD (chronic obstructive pulmonary disease), viral orbacterial infections, influenza, allergies, cystic fibrosis, and otherrespiratory ailments as well as diabetes and other insulin resistancedisorders. The dry powder inhalation may be used to deliverlocally-acting agents such as antimicrobials, protease inhibitors, andnucleic acids/oligionucleotides as well as systemic agents such aspeptides like leuprolide and proteins such as insulin. For example,inhaler-based delivery of antimicrobial agents such as antitubercularcompounds, proteins such as insulin for diabetes therapy or otherinsulin-resistance related disorders, peptides such as leuprolideacetate for treatment of prostate cancer and/or endometriosis andnucleic acids or ogligonucleotides for cystic fibrosis gene therapy maybe performed. See e.g. Wolff et al., Generation of Aerosolized Drugs, J.Aerosol. Med. pp. 89-106 (1994). See also U.S. Patent ApplicationPublication No. 20010053761, entitled Method for AdministeringASPB28-Human Insulin and U.S. Patent Application Publication No.20010007853, entitled Method for Administering Monomeric InsulinAnalogs, the contents of which are hereby incorporated by reference asif recited in full herein.

Typical dose amounts of the unitized dry powder mixture dispersed in theinhalers may vary depending on the patient size, the systemic target,and the particular drug(s). A conventional exemplary dry powder doseamount for an average adult is less than about 50 mg, typically betweenabout 10-30 mg and for an average adolescent pediatric subject istypically from about 5-10 mg. A typical dose concentration may bebetween about 1-2%. Exemplary dry powder drugs include, but are notlimited to, albuterol, fluticasone, beclamethasone, cromolyn,terbutaline, fenoterol, β-agonists (including long-acting β-agonists),salmeterol, formoterol, cortico-steroids and glucocorticoids.

In certain embodiments, the administered bolus or dose can be formulatedwith an increase in concentration (an increased percentage of activeconstituents) over conventional blends. Further, the dry powderformulations may be configured as a smaller administrable dose comparedto the conventional 10-25 mg doses. For example, each administrable drypowder dose may be on the order of less than about 60-70% of that ofconventional doses. In certain particular embodiments, using the activedispersal systems provided by certain embodiments of the DPIconfigurations of the instant invention, the adult dose may be reducedto under about 15 mg, such as between about 10 μg-10 mg, and moretypically between about 50 μg-10 mg. The active constituent(s)concentration may be between about 5-10%. In other embodiments, activeconstituent concentrations can be in the range of between about 10-20%,20-25%, or even larger. In particular embodiments, such as for nasalinhalation, target dose amounts may be between about 12-100 μg.

In certain particular embodiments, during dose dispensing, the drypowder in a particular drug compartment or blister may be formulated inhigh concentrations of an active pharmaceutical constituent(s)substantially without additives (such as excipients). As used herein,“substantially without additives” means that the dry powder is in asubstantially pure active formulation with only minimal amounts of othernon-biopharmacological active ingredients. The term “minimal amounts”means that the non-active ingredients may be present, but are present ingreatly reduced amounts, relative to the active ingredient(s), such thatthey comprise less than about 10%, and preferably less than about 5%, ofthe dispensed dry powder formulation, and, in certain embodiments, thenon-active ingredients are present in only trace amounts.

In some embodiments, the unit dose amount of dry powder held in arespective microcartridge is less than about 10 mg, typically about 5 mgof blended drug and lactose or other additive (e.g., 5 mg LAC), fortreating pulmonary conditions such as asthma. Insulin may be provided inquantities of about 4 mg or less, typically about 3.6 mg of pureinsulin. The dry powder may be inserted into a microcartridge (orcapsule or other suitable container) in a “compressed” or partiallycompressed manner or may be provided as free flowing particulates.

Some embodiments of the invention are directed to inhalers that candeliver multiple different drugs for combination delivery. For example,the inhalers can be configured to provide 60 doses of two differentdrugs (in the same or different unit amounts) for a total of 120individual unit doses. This typically equates to a 30-day or 60-daysupply. In other embodiments, the inhalers can be configured to hold 120doses of the same drug, in the same or different unit amounts, which canbe a 120-day supply (for single daily treatments).

Turning now to the figures, FIG. 1 illustrates an example of amulti-dose inhaler 10. The inhaler 10 is typically disposable after itspre-loaded medicines are dispensed. However, in certain embodiments, theinhaler can be reloaded by a manufacturer, pharmacist or by the use. Theinhaler 10 includes an inhalation port 10 p. The inhaler 10 can includean actuator (shown as an externally accessible lever) 15 that can beused to activate the device. The actuator 15 can comprise a knob,switch, slider, crank or other mechanical or electromechanical device.As will be discussed below, in some embodiments, the actuator 15 can beused to advance a microcartridge 25 (FIG. 2A) into position in aninhalation chamber 10 c (FIGS. 6A and 7) in fluid communication with theinhalation port 10 p. In other embodiments, the actuator 15 may resideinternal to the device and an electronic switch (i.e., on/off switch)can be used to activate the device and/or actuator 15. However, as notedabove, in other embodiments, other mechanisms that do not require leversor that employ alternate configurations of levers may be used toactivate and/or deploy a microcartridge 25 (FIG. 2A) into position inthe inhalation chamber 10 c.

In some embodiments, the mouthpiece port 10 p and an air inlet port (notshown) may be spaced apart about a distance of between about 12-127 mm(about 0.5-5 inches). The inhaler 10 may have a relatively short airintake airpath (measured from where an air intake is disposed to theinhalation port 10 p), such as between about 12-25.4 mm, or a longerairpath, and typically between about 50-127 mm (about 2-5 inches). Theshorter airpath can be defined to include a short tubular airpathextending between the dry powder release location and the inhalationmouthpiece with a turbulence promoter segment that inhibitsagglomeration that merges into the inhaler mouthpiece (not shown). Thelonger airpath may extend across a major portion or substantially all ofa width or length of the inhaler body. For a more detailed discussion ofsuitable turbulence promoter configurations, see PCT/US2005/032492,entitled, Dry Powder Inhalers That Inhibit Agglomeration, RelatedDevices and Methods, the contents of which are hereby incorporated byreference as if recited in full herein.

The inhaler 10 can have a body that is a portable, relatively compact“pocket-sized” configuration. In some embodiments, the inhaler body canhave a width/length that is less than about 115 mm (about 4.5 inches),typically less than about 89 mm (about 3.5 inches), and athickness/depth of less than about 51 mm (about 2 inches), typicallyless than about 38 mm (about 1.5 inches). The inhaler body can also beconfigured to be generally planar on opposing primary surfaces tofacilitate pocket storage.

The inhaler 10 can also include a display 11 and, optionally, a userinput. The display 11 can indicate the number of doses remaining or thenumber of doses used. The user input may include a “+” and a “−” inputkey (not shown). The user input can comprise contact pads, a touchscreen or other input means, including a numeric entry device which canbe used to track the amount of unitized bolus amounts of a target bolusamount of a drug needed by a user.

FIG. 2A illustrates that the inhaler 10 can include a first primarytravel path 30 having a curvilinear segment 30 s (typically a spiralingsegment) with an inner lane 30 i and outer lane 30 o, and as shown, amedial lane 30 m. Additional or lesser numbers of lanes may be used.Each lane is defined by a channel 30 ch that is sized and configured tohold the microcartridges 25 in single-file formation. The channel 30 chtypically includes upstanding sidewalls 30 u (FIG. 4A) and a floor andthe microcartridges 25 can slide along the channel 30 ch, travelingcounterclockwise from the outer lane to the inner lane to a dispensingposition in the inhalation chamber 10 c. Alternatively, themicrocartridges 25 can be configured to travel clockwise with thedispensing path adjusted accordingly. The curvilinear segment 30 s mayinclude a substantially horizontal orientation as shown.

The microcartridges 25 can be captured in the channel 30 ch andconfigured to slidably advance therein. The microcartridges 25 may beconfigured to reside above the floor or may slidably travel over thefloor. As shown, at least a majority of the microcartridges 25 snuglyabut neighboring microcartridges 25. “Dummy” (empty microcartridges or“blank” members) can be used in certain locations of the travel path(such as after the last “full” microcartridge). As will be discussedfurther below, one or more compression springs 125 (FIG. 12) can beplaced in the channel 30 ch and move with the proximately positionedmembers along the travel path 30. The compression spring 125 can providekinetic energy that can help push the forward cartridges along.

In operation, the inhaler 10 is loaded with “full” microcartridges 25.It is noted that the term “full” refers to the container having adesired amount, which may not completely fill the internal sealed volumeof the container 25. The microcartridges 25 are configured to slidablyadvance in the first travel path channel 30 ch with the outer lane 30 omerging into the medial lane 30 m, which merges to the inner lane 30 i.

Thus, the first primary travel path 30 can hold a queue of loadedmicrocartridges 25 on a first level 41 (such as an upper level) of aninhaler 10. At least some of the loaded or full microcartridges 25,including those in the medial and outer lanes, 30 m, 30 o, can seriallytravel greater than one revolution in a first tier or level of theinhaler 10 before advancing to the dispensing lane and into theinhalation chamber 10 c. The tier or level can be substantially planaror may be non-planar. Those microcartridges 25 pre-loaded in the innerlane 30 i can travel a lesser distance than those upstream thereof, suchas about one or less than one revolution before traveling into thedispensing channel (30 d, FIGS. 5, 6). The full microcartridges 25pre-loaded in the outer lane 30 o will travel further than the fullmicrocartridges 25 pre-loaded on the medial or inner lanes 30 m, 30 i,respectively.

FIG. 2B illustrates that the inhaler 10 can include side-by-side travelpaths 30, 31 (rather than and/or in a addition to the multi-level pathsshown in FIG. 2A). As shown, at least a major portion of the two paths30, 31 can be substantially coplanar. The spirals 30 s, 31 s, may beelongated relative to that shown in FIG. 2A and the direction of travelmay be from inner to outer lane rather than from outer to inner lane asdiscussed herein with respect to the embodiment shown in FIG. 2A. Theempty microcartridges 25 as well as cut remnants may be redirected tothe back of a queue or to a trash bin (internal or externallyaccessible) or may be expelled from the inhaler not shown).

FIG. 2C illustrates a top schematic view of another exemplary travelpath configuration. As shown, at least a portion of one travel path 30is behind the other 31, with the dispensing lanes 31 d, 30 d meeting inthe inhalation chamber 10 c. Again, at least a major potion of thetravel paths 30, 31 may reside on a common plane.

FIG. 3A illustrates that the inhaler 10 can include three levels, 41,42, and 43. An exemplary upper level 41 has been described above. Thelower level 43 can include a second primary travel path 31 with acurvilinear channel 31 ch, configured substantially the same as that ofthe first primary travel path 30. In operation, loaded or fullmicrocartridges 25 are pre-loaded in each path 30, 31 and fullmicrocartridges 25 travel in one of the channels 30 ch, 31 ch along atleast a portion of the respective curvilinear lanes 31 s, 30 s. In someembodiments, as shown in FIG. 3B, microcartridges 25 traveling the firstlevel 41 can travel counterclockwise while those traveling the secondlevel 42 can travel clockwise. The travel can be reversed for thecurvilinear portion of each path 30, 31 (not shown). In otherembodiments, the travel in each curvilinear portion of the paths can bethe same direction (also not shown).

Microcartridges 25 from each respective path 30, 31 can travelsubstantially in concert to be delivered concurrently or serially to arespective dispensing lane 30 d, 31 d (FIGS. 5 and 6A), opened, thenmoved in concert or serially into the inhalation chamber 10 c forinhalation delivery. The use of dual primary paths 30, 31 can allow forincreased density loading of microcartridges 25, and/or combination drugdelivery. It is also noted that, although shown as a three-tier orthree-level inhaler 10, a single or dual level configuration, additionallevels (i.e., 4 or more), and/or a single travel path (with increased orthe same number of micro cartridges) rather than dual paths may be used.

Referring to FIG. 4A, in some embodiments, the first path inner lane 30i includes a downwardly oriented ramp 35 that travels down to merge intothe dispensing lane 30 d (FIGS. 5 and 6A) located at a level 42, whichmay be under the upper level 41 of the inhaler 10. Similarly, the secondpath inner lane 31 i can include a ramp 39 that travels up to merge intothe dispensing lane 31 d located at level 42. As shown in FIG. 5, thedispensing lanes 30 d, 31 d travel side by side and travel toward eachin the direction of the holders 75 (FIG. 6A).

As also shown, the inhaler 10 can include a lid 100 that overlies thechannel 30 ch and attaches to the first path 30 to define a ceiling overthe channel 30 ch. The lid 100 can include a ramp segment 135 withincreasing depth in the travel direction that overlies the ramp 35. Theinhaler 10 can also include a floor 101 that underlies the channel 31 chand attaches to the second path 31. The floor 101 can include a rampsegment 138 with increasing height in the direction of travel thatunderlies the ramp 39. The ramp segment 138 extends up into the innerlane 31 i to hold the microcartridges 25 in the channel 31 ch and directthe microcartridges 25 to travel up the ramp 38.

In some embodiments, as shown in FIG. 4B, the levels 41 and 43 can besymmetrically configured so that the lid and floor 100, 101,respectively can have substantially the same configuration. To use asthe lid 100, the member is turned so that the ramps are orienteddownward and aligned with and secured to channel 30 ch; to use as thefloor 101, the member is turned so that the ramps are oriented upwardand aligned with and secured to the adjacent channel 31 ch. Similarly,in some embodiments, the layers 41 and 42 and associated curvilinearsegments 30 s, 31 s are symmetrical. In contrast to level 41, the innerlane 31 i travels up to the level 42 and the return lane from level 42travels down to outer lane 310 at level 43. The inner lanes of eachlayer 41, 42 merge into the respective dispensing lanes 30 d, 31 d atlevel 42. FIG. 4C illustrates the configuration of layer 43, with themicrocartridges traveling clockwise under the layer 41.

In some particular embodiments, the inhaler 10 can be configured toconcurrently dispense combinations of drugs, one from a respectivemicrocartridge 25 from each path 30, 31. As shown in FIG. 6A,microcartridges 25 travel along one of the dispensing lanes 30 d, 31 dto a respective rotating holder 75. The holder 75 includes at least onereceiver 76 that releasably receives a microcartridge 25. As shown, eachholder 75 has three equally spaced (120 degrees from center to center)receivers 76, but lesser or greater numbers may be used. The holder 75rotates to advance the microcartridge 25 held in a respective receiver76 against a blade 175 to cut open the microcartridge 25. Typically, theblade 175 cuts an entire top portion off the microcartridge 25. FIGS. 7and 8 illustrate the top portion of the microcartridge 25 t being cutoff the body 25 b according to some embodiments of the invention. Inother embodiments, the top portion 25 t may be otherwise opened orremoved, and may include other openable configurations, such as apeelable sealant layer, a piercing or puncturing layer or a removablesealant (not shown). Of course, the microcartridge 25 may also be cut atdifferent locations than shown. For example, the blade can cut off alower portion of the body. Alternatively, instead of having the cuttingblade 175 above or below the holder 75, the holder 75 may enclose orhold a greater portion of the microcartridge body therein. As such, theholder 75 may include a slot that allows the blade 175 to cut across themicrocartridge 25 through the holder (not shown).

Referring again to FIG. 6A, after opening, the rotating holder 75rotates to place an open “full” microcartridge 25 in the inhalationchamber 10 e ready for inhalation delivery through the inhalation port10 p (FIG. 1). The rotating holder 75 can hold the open microcartridge25 during inhalation. Then, the rotating holder 75 rotates the receiver76 with the empty microcartridge 25 to return the empty microcartridge(the empty status represented by the “X”) to a cooperating one of thetwo return lanes 30 e, 31 e. The two adjacent holders 75 can rotate inopposing directions. For example, as shown in FIG. 10, the first holder75 ₁ can rotate clockwise while the second 75 ₂ can rotatecounterclockwise. The holders 75 can be configured to rotate in thereverse configuration or in the same direction and may be disposedend-to-end rather than side-to-side or even one above the other.Similarly, the holders can hold lesser or greater numbers ofmicrocartridges. In any event, the empty microcartridge 25 can alignwith the respective cooperating return channel 30 e, 31 e, so that theempty container 25 enters the empty channel 30 e, 31 e. The rear side ofthe discharging receiver 76 can be configured to help push the emptycontainer into the lane. The empty return lanes 30 e, 31 e can mergeback into the same or a different one of the primary travel paths 30,31.

In some embodiments, the cut lids or remnants 25 t can be reattached toa used empty cartridge 25 and retained in the inhaler 25. As such, thecut remnant can be directed to travel back to the, return lane 30 e, 30d and tape or other material can be applied in situ and used toreconnect the two components together (side by side, under or over arespective empty microcartridge) (not shown). In other embodiments, boththe empty microcartridge and the lid 25 t can be directed into a trashbin in the inhaler 10. To facilitate proper sliding in such anembodiment, a sprocket, gear or other drive mechanism can be used tourge the loaded microcartridges 25 forward along the respective travelpath to a dispensing lane 30 d, 31 d.

FIG. 6A illustrates that the inhaler 10 may be configured to generallyconcurrently pick-up a full microcartridge 25 from the dispensing lane30 d and release an empty to the return lane 30 e. FIGS. 6B-6Eillustrate another loading cycle that can pick-up from the dispensinglane 30 d and drop off to the return lane 30 e that may not occur at thesame time using holder 75. In this embodiment, the entry to the returnlane 30 e is disposed closer the entry from the dispensing lane 30 d. Assuch, the holder 75 can have periods during each loading cycle whereonly two of the receiving compartments 75 c hold a microcartridge 25(full or empty). As such, a resilient member 125 may reside in thetravel path 30 ch to compress or relax as appropriate to account for thedifference in numbers of members 25 in the travel lanes.

FIG. 6B illustrates the holder 75 with three cartridges 25, one enteringfrom the dispensing lane 30 d, one in the inhalation chamber 10 c (nowempty or “spent”) and another “spent” or empty microcartridge 25 heldmisaligned with return lane 30 e before aligning with the return lane 30e. This configuration may be the first in an inhalation operation cycle.FIG. 6C illustrates the microcartridge 25 that recently entered theholder 75 in FIG. 6B, is being opened via blade 175, then directed intothe inhalation chamber 10 c as shown in FIGS. 6C-6D. As shown in FIG.6C, during this translation, the microcartridge holder 75 with the emptymicrocartridge 25 (represented by the “X”) shown in FIG. 6B, now alignswith and exits into return lane 30 e. As shown in FIG. 6D, the receivingsegment 75 c between the return and dispensing lanes 30 e, 30 d isvacant for this portion of the loading cycle. FIG. 6E illustrates theopened microcartridge 25 ready for inhalation delivery and the vacantholder 75 c approaching the dispensing lane 30 d for preloading amicrocartridge 25 for the next inhalation sequence at the end of thecurrent inhalation sequence. During the configuration shown in FIG. 6B,the travel path 30 can hold one less microcartridge than during theconfiguration shown in FIG. 6D. As such, the resilient member 125 (FIG.12) may expand briefly during this portion of the loading cycle thencompress during the remaining portions of a respective loading cycle.

In some embodiments, the return lanes 30 e, 31 e are configured so thatthe empty microcartridges 25 from the first dispensing path 30 d returnto the second primary travel path 31 and so that empty microcartridges25 from the second dispensing path 31 d return to the first primarytravel path 30. As such, the return lane 30 e merges into outer lane 310and the return lane 31 e merges into outer lane 30 o of the firstprimary travel path 30.

Referring again to FIG. 5, the return lanes 30 e, 31 e are routedadjacent the dispensing lanes 30 d, 31 d. However, in some embodiments,lane 31 e is directed to travel up to lane 30 o on the first level 41.As shown in FIG. 5, the return lane 31 e include an upwardly rampedfloor 39. As shown in FIG. 4A, the top 100 can include a correspondingmating outer ramp segment 139 that decreases in depth in the directionof travel to cause the lane 31 e to merge with outer lane 30 o.Similarly, the bottom 101 can include a corresponding outer ramp 136that decreases in height in the direction of travel to cause the lane 30e to merge with 31 o.

FIG. 9 illustrates a method of operating an inhaler. As shown, inoperation, a plurality of snugly abutting sealed microcartridges loadedwith a meted amount of a first dry powder are slidably advanced(substantially in concert) along a first curvilinear channel associatedwith a first travel path so that at least some of the respective loadedmicrocartridges travel greater than one revolution in a first level(block 200).

Optionally, at least some of the loaded microcartridges can be directedto travel for dispensing in an inhalation chamber after travelinggreater than one revolution in the first level (block 203). In someembodiments, the first travel path channel defines closely spaced,serially traveled, spiraling travel lanes, and at least some (typicallyat least a majority) of the microcartridges travel greater than 2revolutions in a first level in the spiraling lanes before moving to asecond level for dispensing (block 205).

In particular embodiments, a plurality of snugly abutting sealedmicrocartridges loaded with a meted amount of a second dry powder areconcurrently slid in concert along a second curvilinear channelassociated with a second travel path disposed under the first travelpath so that at least some of the respective loaded microcartridgestherein travel greater than one revolution in a second level residingunder the first level (block 206). In some embodiments, first and seconddry powders are substantially concurrently released from respectivemicrocartridges to a user, whereby the first and second dry powders arecombined in situ for a combination drug delivery (block 208). The methodmay also include rotating a loaded sealed microcartridge toward astationary blade to cut an upper portion thereof open, then vibratingthe microcartridge with a predetermined powder-specific vibratorysignal.

FIG. 10 illustrates that the inhalation chamber 10 c can be incommunication with a circuit 90 c that includes a digital signalprocessor 90, a battery 92 and a vibrator member 95. The signalprocessor 90 can be configured to control the activation of and/orotherwise communicate with the vibratory member 95 to promote releaseand/or fluidization of the dry powder during inhalation drug delivery.The signal processor 90 can include modules that provide powder-specificvibratory signals to the powder during inhalation to facilitate areliable inhalation delivery. Although schematically shown downstream ofthe opened microcartridges 25 ₁, 25 ₂, in the inhalation chamber 10 c,the vibrator device 95 may be disposed under, behind (upstream) or abovethe open microcartridges and inside or outside the inhalation chamber 10c. The device 95 can be integrated in the circuit 90 c and disposed incommunication with the cartridges 25 ₁, 25 ₂, in the inhalation chamber10 c, directly and/or indirectly. In other embodiments, the vibratordevice 95 can reside proximate the inhalation chamber 10 c (inside oroutside thereof) and the remainder of the circuit 90 c can reside inanother portion of the inhaler 10. Traces, leads or wires can be used toprovide the electrical connections.

The circuit 90 c can control certain operations of the inhaler 10. Theinhaler 10 can include a computer port (not shown). The port may be, forexample, an RS 232 port, an infrared data association (IrDA) oruniversal serial bus (USB), which may be used to download or uploadselected data from/to the inhaler to a computer application or remotecomputer, such as a clinician or other site. The inhaler 10 can beconfigured to communicate with a clinician or pharmacy for reorders ofmedicines and/or patient compliance. The inhaler 10 may also include asecond peripheral device communication port (not shown).

In some embodiments, the circuit 90 c can include computer program codeand/or computer applications that communicate additional data to a user(optionally to the display) as noted above and/or communicate withanother remote device (the term “remote” including communicating withdevices that are local but typically not connected during normalinhalant use).

In some embodiments, the signal processor 90 can be in communicationwith the vibrator device 95, to generate a priori powder specificexcitation signals. The signal processor can be programmed with or incommunication with an electronic library of a plurality of desired drypowder excitation signals that can be automatically selected by theprocessor 90 corresponding to the drug type/drug disposed therein. Inthis way, customized drug signals can be used to fluidize the drypowder. The circuit 90 c (FIG. 10) can include electronic memory. Theelectronic memory can include, but is not limited to, cache, ROM, PROM,EPROM, EEPROM, flash memory, SRAM, and DRAM. The circuit 90 c caninclude a computer library module of a priori signals for differentdrugs or of the drugs held in the inhaler. If the former, the inhaler 10can select the appropriate one for operation by the inhaler depending onthe drug(s)in therein. The library module may be programmed into thememory.

Examples of excitation signals and selection methodology are describedin co-pending U.S. Patent Application Publication Nos. 2004-0025877-A1and 2004-0123864, the contents of which are hereby incorporated byreference as if recited in full herein. For example, the excitationsignals can be powder specific and employ a carrier frequency modulatedby one or more modulating frequencies (that may be amplitude modulatingfrequencies) that can facilitate fluidic and reliable flow of the drypowder.

The vibratory signal can include a carrier frequency that may be betweenabout 50 Hz to about 1000 Hz, and typically is between about 100 Hz-1000Hz. The carrier frequency may be modified by one or more low modulatingfrequencies (typically between about 10-200 Hz). The frequency of thevibration can be modified to match or correspond to the flowcharacteristics of the dry powder substance held in the package toattempt to reach a resonant frequency(s) to promote uniform drugdispersion into the body. In some embodiments, a non-linearpowder-specific dry powder vibratory energy signal comprises a pluralityof selected frequencies that can be generated (corresponding to theparticular dry powder(s) being currently dispensed) to output theparticular signal corresponding to the dry powder(s) then beingdispensed. As used herein, the term “non-linear” means that thevibratory action or signal applied to the dry powder, directly orindirectly, to deliver a dose of dry powder to a user has an irregularshape or cycle, typically employing multiple superimposed frequencies,and/or a vibratory frequency line shape that has varying amplitudes(peaks) and peak widths over typical standard intervals (per second,minute, etc.) over time. The non-linear vibratory signal input canoperate without a fixed single or steady state repeating amplitude at afixed frequency or cycle. This non-linear vibratory input can be appliedto the microcartridge(s) 25 and/or chamber 10 c to generate a variableamplitude motion (in either a one, two and/or three-dimensionalvibratory motion). The non-linear signal fluidizes the powder in such away that a powder “flow resonance” is generated allowing active flowabledispensing.

In some embodiments, a signal of combined frequencies can be generatedto provide a non-linear signal to improve fluidic flow performance.Selected frequencies can be superimposed to generate a singlesuperposition signal (that may also include weighted amplitudes forcertain of the selected frequencies or adjustments of relativeamplitudes according to the observed frequency distribution). Thus, thevibratory signal can be a derived non-linear oscillatory or vibratoryenergy signal used to dispense a particular dry powder. In certainembodiments, the output signal used to activate the transducer orvibrator device 95 may include a plurality of superpositioned modulatingfrequencies (typically at least three) and a selected carrier frequency.The modulating frequencies can be in the range noted herein (typicallybetween about 10-500 Hz), and, in certain embodiments may include atleast three, and typically about four, superpositioned modulatingfrequencies in the range of between about 10-100 Hz, and more typically,four superpositioned modulating frequencies in the range of betweenabout 10-15 Hz.

The vibrator device 95 can be any suitable vibrator mechanism. Thevibrator device 95 can be configured to vibrate the dry powder in theairflow path 10 a (indicated by arrows in FIG. 10). In some embodiments,the vibrator device 95 can comprise a transducer that is configured tovibrate the opened cartridge(s) 25 holding the dry powder. Examples ofvibrator devices include, but are not limited to, one or more of: (a)ultrasound or other acoustic or sound-based sources (above, below or ataudible wavelengths) that can be used to instantaneously applynon-linear pressure signals onto the dry powder; (b) electrical ormechanical vibration of the walls (sidewalls, ceiling and/or floor) ofthe inhalation flow channel and/or drug cartridge 25, which can includemagnetically induced vibrations and/or deflections (which can useelectromagnets or permanent field magnets); (c) solenoids,piezoelectrically active portions and the like; and (d) oscillating orpulsed gas (airstreams), which can introduce changes in one or more ofvolume flow, linear velocity, and/or pressure. Examples of mechanicaland/or electro-mechanical vibratory devices are described in U.S. Pat.Nos. 5,727,607, 5,909,829 and 5,947,169, the contents of which areincorporated by reference as if recited in full herein. In someparticular embodiments, the vibrator device 95 includes at least onepiezoelectric element, such as a piezoceramic component, and/or apiezoelectric polymer film. Combinations of different vibratingmechanisms can also be used.

In some embodiments, the vibrator device 95 can include a commerciallyavailable miniature transducer from Star Micronics (Shizuoka, Japan),having part number QMB-105PX. The transducer can have resonantfrequencies in the range of between about 400-600 Hz. However, theinhaler 10 may operate the device 95 “off-resonance” such as betweenabout 1-500 Hz and/or generate a non-linear vibratory signal with acarrier frequency and at least one powder-specific modulating frequency.The non-linear signal can include frequencies between 1-5000 Hz. Thevibratory signal output by the device 95 can be powder-specific orcustomized to the powder(s) being dispensed using a priori signals. Iftwo different dry powders are being concurrently dispensed, thevibratory signal can be delivered via a single transducer (with a commonsignal) in communication with each microcartridge 25 in the chamber 10 cor via separate transducers, each capable of delivering a differentvibratory signal to a respective microcartridge 25 in the chamber 10 c.

In certain embodiments, the inhaler 10 can include visible indicia(flashing light or display “error” or alert) and/or can be configured toprovide audible alerts to warn a user that a microcartridge 25 ismisaligned in the inhaler 10 and/or that a dose was properly (and/orimproperly) inhaled or released from the inhaler. For example, certaindry powder dose sizes are formulated so that it can be difficult for auser to know whether they have inhaled the medicament (typically thedose is aerosolized and enters the body with little or no taste and/ortactile feel for confirmation). Thus, a sensor (not shown) can bepositioned in communication with the flow path 10 a in an inhaler andconfigured to be in communication with a digital signal processor ormicrocontroller, each held in or on the inhaler. In operation, thesensor can be configured to detect a selected parameter, such as adifference in weight, a density in the exiting aerosol formulation, andthe like, to confirm that the dose was released.

Referring to FIG. 11A, the rotating holders 75 ₁, 75 ₂ are shown withblades 175 ₁, 175 ₂ thereon. In some embodiments, the blades 175 ₁, 175₂ can be stationary and configured to slice off a top of themicrocartridge 25 in the respective holder 175 rotates toward theinhalation chamber 10 c. FIG. 11A also illustrates the vibrator device95 substantially under and between the holders 75 ₁, 75 ₂ at a medialportion of the inhaler 10. Of course, the blade may optionally translateor one side may translate while the other remains stationary.

In some embodiments, the first holder 175 ₁ rotates clockwise and thesecond holder 175 ₂ rotates counterclockwise, each toward the center ofthe inhaler 10, and the cutting edge 175 c is on an outside edge of therespective blade. Each rotating holder 75 ₁, 75 ₂ can be attached to apost 176 ₁, 176 ₂ and the blade 175 ₁, 175 ₂ can extend across andsubstantially flush with the top surface of the respective holder, withthe respective blade 175 being held in a substantially coplanarorientation with the underlying holder 75. In operation, as a holder 75rotates toward the cutting blade 175, the receiving segment 76 securelyholds the microcartridge 25 therein with the top portion of themicrocartridge 25 extending above the top surface of the curvilinearreceiving segment 76. The holder 75 turns to force the microcartridge 25against the cutting edge 175 c. The cut remnant 25 t portion of themicrocartridge 25 t is directed into a trash bin 300 (FIG. 11B) in theinhaler 10. The cut remnant 25 t is prevented from moving into theinhalation chamber 10 c by the surface of the blade 175 and may travelrearward into a medial portion of the inhaler into the bin 300 (FIG.11B) above the top surface of the blade 175 for accumulation. The trashbin 300 may include a gate 301 that is configured to inhibit remnants 25t from leaving the bin, should the inhaler be dropped, shaken, or turnedupside down.

It is also noted that the remnant 25 t and/or empty microcartridges 25 ecan be discharged from the inhaler 10 after each deliver or at certainintervals. In some embodiments, a releasable externally accessible cupcan be the trash bin 300 which can allow a user to empty as desired (notshown). Optionally, an audio or visual alert can be used to notify auser when to empty the bin 300.

FIG. 12 illustrates an example of a queue of microcartridges 25 in thefirst level 41 in the curvilinear travel path 30 s. In this embodiment,a resilient member 125 can be disposed in each of the travel paths 30,31. The resilient member 125 may comprise a compression spring (asshown), a leaf spring, an elastomeric spring or other type of mechanismconfigured to advance the “full” microcartridges 25. The resilientmember 125 can be configured to impart kinetic and/or potential energyto push the microcartridges 25 upstream thereof along the path. Theresilient member 125 typically resides upstream of the return lanes 30e, 31 e. In some embodiments, the resilient member 125 can expand andcompress a plurality of times during use to compensate for differentnumbers of microcartridges 25 (or dummies) and/or loading patterns in atravel path 30, 31, such as during each holder loading cycle. Forexample, at times when there are three microcartridges in the holder 75(FIGS. 6B, 6C), the member 125 may laterally expand while when there aretwo in the holder 75 (more in the track) (FIG. 6D), the member 125 cancompress. An exemplary length of the compression spring 125, where used,can be between 0.5-2 inches, typically about 1 inch.

As shown, in FIG. 12, the resilient member 125 is typically disposedupstream of the “last” usable dose of medicament in a trailingmicrocartridge 25 t in front of the first “empty” microcartridge 25 e.The location of the resilient member will move during operation as themember travels in the channel 30 ch (or 31 ch). In some embodiments, theinitial position of the resilient member 125 is such that at least arearward portion resides in the return lane 31 e, 30 e. The resilientmember 125 can float in the channel or be attached to structural endmembers having increased rigidity to maintain the member 125 in thechannel.

In addition, dummy members may be placed on either or one end of theresilient member 125 as well. A pin or other retainer member 126 can beused to hold the resilient member in the trailing position. As thereturn lane 31 e becomes full of empty microcartridges 25 e as shown inFIG. 12, the rearward ones push forward ones to travel up to the outerlane 30 o of the curvilinear path 30 s (or if from lane 30 e, the emptymicrocartridges travel down to lane 31 o of path 31 s). The emptycartridges 25 e can travel under a retainer 126 (such as the pin) orother component and push the resilient member 125 forward to forcemicrocartridges upstream thereof to serially travel in the path 30 intothe dispensing lane 30 d (or 31 d). The lower floor can operate in thesame or a substantially similar manner.

The movement of the microcartridges 25 in the inhaler 10 can beprimarily attributed to the high density loading and/or pushing of themicrocartridges 25 along the travel path. The movement can beself-propelled, i.e., the microcartridges 25 or dummies can besubstantially free-floating in the respective channel 30 th, 31 ch in asnug configuration so that empty containers or dummy members push theupstream full ones. In other embodiments, the floors and/or ceilings ofthe channels can rotate and/or indexers, gears or other mechanisms canbe employed to help to move the microcartridges in the travel lanes 30,31.

The channel sidewalls, floors or ceilings as well as the microcartridgescan be formed of a material that has suitable frictional properties toallow sliding without undue friction. For example, the microcartridges25 can comprise a polymer body. In addition, the channels 30 th, 31 chcan be molded and comprise a polymer and/or material with low frictionsurfaces, or alternatively, a low friction (smooth/slick) coating can beapplied to one or more of the floor, bottom or sides of the channel 30th, 31 ch and/or microcartridges 25.

FIG. 13 illustrates one embodiment of a linkage mechanism 150 thatconverts linear movement of a lever-based actuator 15 (FIGS. 1, 15) intorotation of the holders 75 ₁, 75 ₂ (FIG. 10). As shown, the mechanism150 includes a center member 152 that slides forward and rearward inslots 153. The slots 153 help keep the member 152 registered in a medialposition. The member 152 can also include a lateral slot 152 s thatengages a pin 15 p on the lever 15 (FIG. 15) to translate the centermember 152 back and forth. The center member 152 is attached to arms 151₁, 151 ₂ at pivot joints 151 p. The forward portion of arms 151 ₁, 151 ₂are each attached to a slotted arm 77 that merges into cup 75 c. The cup75 rotates the respective holders 75 with the curved receiving segments76. During a single stroke, the arms 151 ₁, 151 ₂ move in the respectiveslot 77 and rotate the cup 75 c about 120 degrees.

FIG. 14 illustrates an exploded view of a cup assembly above the top ofthe cup 75 c. As shown, the cup 75 c includes a receiving cavity 74,which is configured to receive the post 176 and mount the holder 75. Theholder 75 can mount to a gripping ratchet 78 that may reside in the cupcavity 74 and turn the holder 75 to allow movement in one direction. Theratchet member 78 is in communication with a pawl 290 (FIG. 13) that isattached to the housing to force/bias the holder 75 to rotate only inthe desired direction. The cup cavity 74 may rotate through twopositions while the ratchet 78 can rotate through three operativepositions to thereby move the holder 75 through three positions. The cup75 c may also include features that inhibit reverse movement.

FIGS. 15-17 illustrate that the arms 151 ₁, 151 ₂ cooperate with andmove in and out of a slot 251 s in a housing member 251 from a rest toan extended position. In operation, a lever 15 resides in slot 152 swhich, when moved forward, moves the center member 152 forward. Thisaction causes tip portions 151 t of the arms to contact the perimeterwall of the slot 251 s, which concurrently pivots both of the arm tips151 t upward and forces the downstream end portions 151 d of therespective arms 151 ₁, 151 ₂ to pivot outward away from each other. Asthe tips 151 d rotate outward, they also move inward along slots 77toward cups 75 c to rotate the cups 75 c outward away from each other.The rotation shown is about 120 degrees. Other configurations may beused to provide different rotational operation such as if lesser orgreater degrees of rotation are desired.

As shown in FIG. 15, the lever 15 is attached to center member 152 viapin 15 p that resides in slot 152 s. As the lever 15 moves forward, itcauses a sequence of movements of the linkage mechanism 150 thatconverts the linear movement of the lever 15 into a 120-degree rotationof two holders 75 ₁, 75 ₂. As shown, a spring 15 s can be attached tothe lever 15 to bias the lever to return to a start configuration.

Each actuation cycle of the mechanism 150 is configured to move an emptymicrocartridge 25 to the respective return lane 30 e, 31 e (FIGS. 6A,6B), obtain a full microcartridge 25, open a full microcartridge andindex the opened full microcartridge into an inhalation position in theinhaler 10 using a single actuation of the lever 15 (back and forth,although rotation is typically only caused by forward motion of thelever). Forward movement of the lever 15 moves the cup 75 c about 120degrees, and a rearward motion places the mechanism 150 in a readyposition for the next inhalation dispensing cycle.

FIG. 18 illustrates one embodiment of a sealed microcartridge 25. Asshown, the microcartridge includes a body 25 b with a holding cavity anda lid 25 l.

The lid 25 l and body 25 b can be formed of the same material ordifferent (compatible materials). The lid and/or body of themicrocartridge 25 may be molded to have a substantially common thicknesssufficient to inhibit moisture and/or oxygen penetration for the desiredshelf life. In some embodiments, the microcartridge 25 is formed of anelatomeric material, such as a polymer copolymer or derivatires thereof,and in particular embodiments is formed of a thermoset polymer such aspolypropylene (antistatic) and/or polyethylene (antistatic). Examples ofsuitable material include, but are not limited to, RTP CompanyPermastat100, Martex HGL-120-01, and Borealis HJ320MO. The lid 25 l isattached via any suitable means such as laser welding, ultrasonicwelding, friction welding, high frequency welding, brazing, adhesive, orotherwise to affix the lid into position. In some embodiments, the lid25 l can be pressed onto the body 25 b and sealably attached to the bodywithout adhesives. The sealed body may be dipped sprayed or otherwisecoated, layered or sealed with another material (metal and/or polymer orother desired material) to enhance the shelf-life or provide additionalmoisture or oxygen penetration resistance.

The microcartridge 25 can be configured to hold suitable dry powderunit, bolus, or sub-unit doses of medicament therein. In particularembodiments, the microcartridges 25 are configured to deliver metedamounts of a combination of two different medicaments. The sealedmicrocartridge 25 can be configured so that the water vapor transmissionrate can be less than about 1.0 g/100 in²/24 hours, typically less thanabout 0.6 g/100 in²/24 hours. The microcartridge 25 can have an oxygentransmission rate that is suitable for the dry powder held therein. Themicrocartridges 25 can be configured with a stable shelf life of betweenabout 1-5 years, typically about 4 years.

The microcartridge 25 can have a volume (prior to filling and sealing)that is less than about 24 mm³, typically less than about 15 mm³. Thenominal percent filled at 100% dose, nominal density can be about 40%open to about 75% sealed. The powder bulk density can be about 1 g/cm³while the power nominal density when filled (for reference) can be about0.5 g/cm³. The maximum compression of a drug by filling and sealing inthe microcartridge 25 can be less than about 5%, typically less thanabout 2%. The maximum heating of drug during the filling and sealing canbe maintained to a desirable level so as not to affect the efficacy ofthe drug or the formulation.

In some embodiments, a meted amount of dry powder is placed in the openmicrocartridge body 25 b, which is then sealed with the rigid lid 25 lattachment via ultrasonic welding to form the sealed “full”microcartridge. Alternatively, other lid or sealant configurations maybe used such as foil, TEDLAR or other suitable materials, includinglaminates. The microcartridge 25 can be configured to hold about 5 mgtotal weight of a blended drug. The 5 mg may include lactose or anotherexcipient. During filling, the drug can be compacted in a pre-meteredamount and inserted into the microcartridge cavity.

FIGS. 19A-19D illustrate a filling and sealing sequence ofmicrocartridges 25. As shown, the body 25 b can have a curved (concave)bottom with a perimeter lip 25 p or may be substantially planar orconvex (not shown). In some other embodiments, the microcartridge 25 mayhave a semi-spherical or dome shaped lid (not shown), In some otherembodiments, the entire microcartridge 25 may be substantially sphericaland configured to roll (also not shown).

FIG. 21 illustrates a method of providing meted dose microcartridges foruse in dry powder inhalers. The methods include providing asubstantially rigid elastomeric microcartridge body (block 220) andinserting a meted amount of dry powder suitable for inhalation delivery(block 222). Then a substantially rigid top is attached to the body toseal the dry powder therein (block 225). The top can comprise asubstantially rigid elastomeric lid (block 227). Optionally, externallyvisible indicia can be provided on the body to indicate the type ofpowder and/or dose amount (block 221). The inserting step can includeinserting a meted (which may be unit dose) amount of between about 0.1mg. to about 50 mg of dry powder (block 223).

In embodiments dispensing combination drugs, the microcartridges 25include externally visual indicia that correspond to a drug therein, toallow manufacturers and automated devices to be able to easily recognizethe drug type inserted into the inhaler. This should also facilitatevisual confirmation that the correct drugs are in the correct respectivechannel in the inhaler. The inhaler body can be configured to have thematching indicia on the upper and lower sides of the body so that a“green” cartridge 25 resides in the green portion (channel) and a“white” microcartridge in the white portion (channel). Thus, thechannels 30 ch, 31 ch and/or respective lid or floors 100, 101 (FIG. 4A)can include corresponding indicia. Thus, the inhalers can be provided indifferent color combinations corresponding to a dose or drug type heldtherein. A manufacturing facility can more readily assemble the correctdrugs in the correct inhaler and inspect for conformance to themanufacturing lot. Thus, if a low dose of drug one in a microcartridgein a combination inhaler (having a color such as pink) is held in awhite inhaler channel intended for a high dose “white” microcartridge,an operator can readily pull the non-compliant inhaler from the assemblyline. Thus, the inhaler can be configured with mating components thatcan be color coded, marked, or otherwise visually marked for differentdoses and/or different types of drugs. The color-coding can be for themicrocartridges 25 and each of the channels 30 ch, 31 ch and/or levels41, 43 and/or other visually accessible inhaler body portions. Thecolor-coding can be a pattern (strip, circles, etc.) or a solid colorbody or lid.

Also, as discussed above, and shown for example, in FIGS. 11A and 12,when loaded in the inhaler 10, the microcartridges 25 can be discretebodies that are detached from each other. However, in some embodiments,as shown for example in FIG. 20A, tape 350 can be used to connect themicrocartridges 25. The tape 350 can help load the cartridges 25 in adesired alignment in the curvilinear channel 30 ch, 31 ch. The tape 350may be single sided tape that can be removed once the containers 25 areheld in the channel in the desired loading density. The tape 350 may becolor coded to the particular drug/dose as well to facilitate correctloading of the inhaler 10. The channels can be configured to retain themicrocartridges 25 from vertical movement, so that the tape or othersubstrate can be pulled off leaving the microcartridges 25 in position.That is, a “string” or link of attached microcartridges can be pulledinto the spiral portion of the travel path, then the tape can beremoved. In other embodiments, the tape 350 can remain and the bodies 25separated from the tape 350 as they are rotated in the holder 75 or inadvance of movement into the holder 75. As shown in FIG. 20B, themicrocartridges 25 can be attached on a side rather than a top or bottomand some space may remain between neighboring microcartridges 25. Ofcourse, the bodies 25 may alternatively be arranged to abut as well. Foreach of the embodiments shown in FIGS. 20A and 20B, the tape orsubstrate 350 can remain on the microcartridges 25 and be used to rollor pull the microcartridges 25 along a portion, or substantially all, ofthe travel path to the inhalation chamber 10 c.

While the present invention is illustrated, for example, with referenceto particular divisions of programs, functions and memories, the presentinvention should not be construed as limited to such logical divisions.Thus, the present invention(s) should not be construed as limited to theconfigurations shown and described, as the invention(s) is intended toencompass any configuration capable of carrying out the operationsdescribed herein.

Certain embodiments may be particularly suitable for dispensingmedication to diabetic patients, cystic fibrosis patients and/orpatients having diseases or impairments where variable bolus medicamentsare desired. Other embodiments may be particularly suitable fordispensing narcotics, hormones and/or infertility treatments.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. In the claims, means-plus-function clauses, where used, areintended to cover the structures described herein as performing therecited function and not only structural equivalents but also equivalentstructures. Therefore, it is to be understood that the foregoing isillustrative of the present invention and is not to be construed aslimited to the specific embodiments disclosed, and that modifications tothe disclosed embodiments, as well as other embodiments, are intended tobe included within the scope of the appended claims. The invention isdefined by the following claims, with equivalents of the claims to beincluded therein.

1. A method of operating a dry powder inhaler to expel inhalablemedicaments to a user, comprising: slidably advancing a plurality ofsealed substantially rigid microcartridges, each having a first drypowder, along a first spiral shaped travel path so that at least some ofthe respective microcartridges travel greater than one revolution in afirst level of the inhaler; then directing the microcartridges toserially travel to an inhalation chamber after traveling greater thanone revolution in the first level; and opening at least onemicrocartridge in or proximate to the inhalation chamber to therebyallow the dry powder in the respective opened microcartridge in theinhalation chamber to be inhaled by a user.
 2. A method according toclaim 1, wherein the first travel path channels are closely spaced apartspiraling travel lanes, wherein the slidably advancing step is carriedout by directing microcartridges to serially travel the travel lanesfrom an outside channel to an inside channel or from an inside channelto an outside channel, wherein at least some of the microcartridgestravel greater than 2 revolutions in a first level travel lanes beforemoving to a second level of the inhaler, residing above or below thefirst level.
 3. A method according to claim 1, wherein the slidablyadvancing step is carried out using kinetic energy to cause themicrocartridges to push neighboring microcartridges to travel singlefile and in abutting contact.
 4. A method according to claim 3, themethod further comprising slidably advancing a plurality ofmicrocartridges with a second dry powder along a second spiral shapedtravel path so that at least some of the respective microcartridgestherein travel greater than one revolution in the second travel pathchannel before moving to the inhalation chamber.
 5. A method accordingto claim 4, further comprising releasing first and second dry powdersfrom respective micro cartridges, one obtained from each of the firstand second travel paths in response to the slidably advancing steps, toa user generally concurrently whereby the first and second dry powdersare combined in situ for a combination drug delivery.
 6. A methodaccording to claim 1, wherein the opening step comprises automaticallyrotating a sealed microcartridge toward a cutting blade and cutting anupper portion thereof open, then automatically positioning the openmicrocartridge in the inhalation chamber.
 7. A method according to claim6, further comprising vibrating the microcartridge with a vibratorysignal before and/or after the cutting step.
 8. A method according toclaim 4, further comprising, after the opening step, directing emptymicrocartridges to return to a trailing end portion of a queue ofmicrocartridges in one of the first and second travel paths, andwherein, during the slidably advancing step, the microcartridges arefree floating and at least some snugly abut neighboring microcartridgesin a channel having a single unit width.
 9. A method according to claim8, wherein the microcartridges in the first travel path travelcounterclockwise, and wherein the microcartridges in the second travelpath travel clockwise.
 10. A method according to claim 6, wherein therotating is carried out such that microcartridges from the first travelpath rotate in a first microcartridge holder in one of a clockwise orcounterclockwise direction while held substantially upright to cut off aportion of the microcartridge, and microcartridges from the secondtravel path are rotated in a second microcartridge holder in an opposingdirection while held substantially upright to cut off a portion of themicrocartridge.
 11. A method according to claim 10, further comprising,after the cutting, automatically trapping cut remnants from themicrocartridge in a holding receptacle in the inhaler away from theinhalation chamber.
 12. A method according to claim 1, wherein theopening step comprises advancing an actuator to rotate a microcartridgeholder holding a respective microcartidge to slice open a top portionthereof in response to contact with a cutting blade, then positioningthe open microcartridge in the inhalation chamber for inhalation of drypowder.
 13. A method according to claim 12, wherein, the microcartridgeholder is configured to hold both an empty and a sealed microcartridgeand the rotating step automatically positions the empty microcartridgein a return queue lane in the inhaler where empty microcartridges pushother microcartridges along the first travel path.
 14. A methodaccording to claim 1, wherein the inhaler first travel path isconfigured to each hold about 60 microcartridges.
 15. A method accordingto claim 1, wherein the microcartridges sealably hold between about 0.1mg to about 50 mg of dry powder therein.
 16. A method according to claim15, wherein the dry powder amount is between about 1-10 mg.
 17. A methodof operating a dry powder inhaler having a first generally planar spiraltravel path, wherein the first spiral travel path has a plurality ofadjacent curvilinear channels forming lanes with respective laterallyspaced apart upstanding sidewalls, including an inner lane and an outerlane, the method comprising: slidably advancing a plurality of discretesealed microcartridges with substantially rigid bodies along the firsttravel path toward an inhalation chamber that merges into an inhalationoutput port, wherein the microcartridges are oriented in the channels sothat outer walls thereof reside proximate respective laterally spacedapart channel sidewalls and bottoms thereof face a floor of the channel,and wherein outer walls of neighboring microcartridges are in abuttingcontact during the slidably advancing step.
 18. A method according toclaim 17, wherein the dry powder inhaler has a second generally planarspiral travel path that resides above the first generally planar spiraltravel path, wherein the second spiral travel path also has a pluralityof curvilinear channels forming lanes with upstanding sidewalls,including an inner lane and an outer lane, the method furthercomprising: slidably advancing microcartridges along the second travelpath, then along the first travel path, then toward the inhalationchamber that merges into the inhalation output port.
 19. A methodaccording to claim 17, wherein the discrete microcartridges travel insingle file, captured between the channel sidewalls, and wherein theslidably advancing step is carried out by neighboring microcartridgesslidably pushing microcartridges downstream thereof in a dispensingdirection toward an inner lane of the first spiral travel path thatmerges into a dispensing lane that leads to the inhalation chamber.